The AIDS opportunistic infection tuberculosis infects one-third of the world's population and, with malaria, ranks among the 12 leading causes for loss of Disability-Adjusted Life Years (“DALYs”). The rapid spread of drug-resistant strains of tuberculosis and malaria, coupled with the extremely limited numbers of drugs available to treat these diseases, has created an urgent need for novel therapeutic agents with new modes of action to counter these impeding threats.
Despite a significant mortality reduction in the United States and Europe from infectious diseases over the last century the last two decades have shown mortality increases that indicate the need for constant vigilance. See, Armstrong, G. L.; Conn, L. A.; Pinner, R. W., “Trends in Infectious Disease Mortality in the United States During the 20th Century,” JAMA 1999, 281, 61-66. An unforeseeable trend from 1980 to the early 1990's resulted in an astonishing 58% increase in mortality rates associated with infectious diseases. Numerous spikes in the mortality rates over the last century from infectious diseases indicate how quickly a contagious disease can move through a population. The seriousness is further compounded with increases in drug resistance and outbreaks of diseases like avian influenza that have no previous history of being infective to humans. See, “Centers for Disease Control and Prevention, Update: Isolation of Avian Influenza A (H5N1) Viruses From Humans in Hong Kong,” 1997-98, Morbidity and Mortality Weekly Reports 1998, 46, 1245-47.
The risk of malaria now exists in 100 countries and territories, with 92 of these facing the malignant form of the disease (Plasmodium falciparum). Over 45% of the world population lives in areas of the world where malaria is endemic. Globally, there are 300-500 million clinical cases annually, with 1.5-2.7 million deaths associated with malaria. See, http://www.who.int/ctd/html/malaria.html (2000). Most of the annual deaths occur among children under five years of age. Despite the initial success of the World Health Organization's program to eradicate malaria globally during the 1950's and 1960's, it has become increasingly clear that these attempts have faltered due to increasing resistance of the malarial parasites to commonly used drugs and of the mosquito to insecticides. The estimated number of new infections has now reached their original levels, many of these being “malignant” malaria caused by the most dangerous malarial parasite, P. falciparum. 
In recent years the marine environment has emerged as a promising source for new lead drugs to combat this devastating disease. See, El Sayed, K. A.; Dunbar, C. D.; Goins, K. D.; Cordova, C. R.; Perry, T. L.; Wesson, K. J.; Sanders, S. C.; Janus, S. A.; Hamann, M. T. The Marine Environment: A Resource for Prototype Antimalarial Agents, J. Nat. Toxins. 1996, 5, 261-285; Nasu, S. S.; Yeung, B. K. S.; M. T. Hamann; Scheuer, P. J.; Kelly-Borges, M.; Goins, K. D, Puupehenone-Related Metabolites From Hawaiian Sponge, Hyrtios spp., J. Org. Chem. 1995, 60, 7290-7292. The fairly common and easily isolated marine alkaloids known as the manzamines show dramatic and unexpected improvements in activity against malaria in mice as noted above. See, Ang, K. K. H.; Homes, M. J.; Higa, T.; Hamann, M. T.; Kara, U. A. K., “In vivo Antimalarial Activity of the Beta-Carboline Alkaloid Manzamine A,” Antimicrob. Agents and Chemother. 2000, 44, 1645-1649.
Although malaria is not considered an opportunistic infection in HIV-infected patients it has been shown that HIV positive individuals are more susceptible to P. falciparum and become more symptomatic. See, Verhoeff, F. H.; Brabin, B. J.; Hart, C. A.; Chimsuku, L.; Kazembe, P.; Broadhead, R. L., “Increased Prevalence of Malaria in HIV-Infected Pregnant Women and its For Malaria Control,” Trop Med Int Health 1999, 4, 512. See also, French, N.; Gilks, C., “HIV and malaria, do they interact?,” Trans R Soc Trop Med Hyg 2000, 94, 23337. In addition, plasma viral loads have been shown to be higher in acutely infected malaria patients with HIV (see, Hoffman, I. F.; Jere; C. S.; Taylor, T. E., “The Effect of Plasmodium falciparum Malaria on HIV-1 RNA Blood Plasma Concentration, AIDS 1999, 13, 487494) and malaria infections have been shown to induce virus expression in HIV transgenic mice. See, Freitag, C.; Chougnet, C.; Schito, M.; Near, K. A.; Shearer, G. M.; Li, C.; Langhorne, J.; Sher, A., “Malaria Infection Induces Virus Expression in Human Immunodeficiency Virus Transgenic Mice by CD4 T Cell-Dependent Immune Activation,” J. Infectious Diseases, 2001, 183, 1260-1268.
Tuberculosis (Mtb) remains today one of the most infectious diseases in the world. It is estimated that one-third of the world's population is infected by the tubercular organism, which claims the lives of 2-3 million people each year. In the large majority of those infected the infection remains latent, with only 10 percent ever developing active tuberculosis. The organism, however, is opportunistic and emerges to strike those with weakened immune systems, such as the elderly, AIDS patients, and people suffering from malnutrition. The infecting organism is a rod-shaped bacterium known as Mycobacterium tuberculosis. 
Because relatively few drugs have been found satisfactory for the treatment of tuberculosis the occurrence of drug resistant tubercular bacilli looms with a frightening potential. Bacterial resistance to each of the presently available antituberculosis drugs has been observed, even with their combined use. The combined use of treatments involving rifampin and pyrazinamide has been shown to be potentially lethal. See, Morbidity and Mortality Weekly Reports 2001, 50, 289-291.
Once ranked among the most common causes of death, improved methods of prevention, detection, diagnosis, and treatment have greatly reduced the number of people who get tuberculosis and the number of people who die from this disease. In the last ten years, however, tuberculosis has re-emerged as a major concern. That is, after decades of steady decline there has been resurgence in the number of new cases. Reports have appeared concerning clusters of the disease, especially the more dangerous multidrug-resistant (MDR-TB) forms, occurring in several hospitals and prisons. The complication of multi-drug resistance constitutes one of the major causes of therapeutic failure. See, Hutton, M. D., Stead, W. W., Cauthen, G. M., et al., “Nosocomial Transmission of Tuberculosis Associated With a Draining Abscess,” J. Infect. Dis., 1990, 161, 286-295; Selwyn, P. A., “Tuberculosis in the AIDS Era: a New Threat From an Old Disease,” N.Y. J. Med., 1991, 91, 233-235; Selwyn, P. A., Hartel, D., Lewis, V. A., et al., “A Prospective Study of the Risk of Tuberculosis Among Intravenous Drug Users With Human Immunodeficiency Virus Infection,” New England J. Med., 1989, 320, 545-550; Starke, J. R., “Prevention of Tuberculosis,” Seminars in Respiratory Infections, 1989, 4 (4), 318-325. This raises the specter of a serious accelerating public health problem with the potential to spread regionally and nationally. In 1953, there were 84,304 reported cases of TB. See, Bloch, A. B., Rieder, H. L. and Kelly, G. D., The Epidemiology of Tuberculosis in the United States, Seminars in Respiratory Infections, 1989, 4(3), 157-170. For the next 31 years the number of new cases evidenced a steady downward drift. By 1984 the number of new incidences each year had declined 74 percent. The downward trend then reversed. During the 1980's, outbreaks of tuberculosis began to increase in the United States, partly as a result of the spread of AIDS. The disease also struck growing numbers of homeless people and drug addicts. By the late 1980's, 25,000 new cases were being reported annually, with about 2,000 deaths from the disease. By 1992, instances of the disease had increased 20 percent over the number of cases in 1985.
AIDS has been an important factor in the resurgence of tuberculosis. TB is one of the most common opportunistic infections of AIDS, and is the AIDS-defining condition in about 30 percent of AIDS cases. See, Harries, A. D., Tuberculosis and Human Immunodeficiency Virus Infection in Developing Countries,” Lancet, 1990, 335, 387-390. Over the next decade this could lead to a dramatic increase in the number of deaths from TB in places where TB and AIDS are endemic. According to the World Health Organization (WHO), 4 million people worldwide are infected with both the tubercular bacillus and HIV. See, Raviglione, M. C., Narain, J. P., and Kocchi, A., “HIV-associated Tuberculosis in Developing Countries: Clinical Features, Diagnosis, and Treatment,” Bulletin of the International Union Against Tuberculosis Lung Disease, 1992, 70 (4), 515-526. Treating TB in patients with HIV has added complexities. Coexisting infections and other AIDS-associated disorders require treatments that may interact with the antibiotics used to treat TB. High rates of toxicity and drug reactions, especially with rifampin, have been reported in TB patients with AIDS. See, FitzGerald, J. M., Grzybowski, S., and Allen, E. A., “The Impact of Human Immunodeficiency Virus Infection on Tuberculosis And its Control,” Chest, 1991, 100 (1), 191-200; Nolan, C. M., “Failure of Therapy for Tuberculosis in Human Immunodeficiency Virus Infection,” Am. J. Med. Sc., 1992, 304 (3), 168-173; Small, P. M., Schecter, G. F., Goodman, P. C., et al., “Treatment of Tuberculosis in Patients With Advanced Human Immunodeficiency Virus Infection,” New England J. Med., 1991, 324, 289-294. Another complicating factor is that the various extrapulmonary types of TB appear to be more common among patients with HIV. See, Fischl, M. A., Daikos, G. L., Uttamchandani, R. B., et al., “Clinical Presentation And Outcome Of Patients With HIV Infection And Tuberculosis Caused By Multi-Drug Resistant Bacilli,” Ann. Int. Med., 1992, 117, 184-190; Pitchenik, A. E., and Fertel, D., “Tuberculosis and Nontuberculosis Mycobacterial Disease,” Med. Clin. N. Am., 1992, 76 (1), 121-171. The risk of developing tuberculosis among HIV positive patients is over 100 times higher than among HIV negative individuals. Tuberculosis is a unique, serious disease. Unlike other diseases associated with AIDS, it may be spread by airborne transmission to adults and children who are not at risk of AIDS. In 1992, worldwide tuberculosis mortality was two million, in addition to the report of 8 million new cases.
Resistance to current antituberculosis therapy is another threatening problem. Multi-drug-resistant strains of M. tuberculosis, resistant to as many as nine drugs, are 50-80% fatal even with intensive treatment. In the U.S., drug-resistant strains have been identified in seventeen states since 1989. Isoniazid resistance in the U.S. is present in 5.3% and secondary resistance in 19.4% of isolates, while the figures for rifampin are 0.6% and 3.2%, respectively. The resurgence of drug-resistant-tuberculosis has initiated a renewal of interest in a strategic search for new prototype leads. The oceans, with their unique and wide range of biodiversity, generating chemically diverse metabolites, emerge as an outstanding resource for new agents with anti-Mycobacterial activity. See, El Sayed, K. A.; Bartyzel, P.; Shen, X.; Perry, T. P.; Zjawiony, J. K.; and M. T. Hamann, “Marine Natural Products as Antituberculosis agents.” Tetrahedron 2000, 56, 949-953.
Presently available antimalarial drugs include the quinoline derivative quinine and its (+) diastereoisomer (with respect to the asterisked carbon), quinidine (see Formula I below), which are natural quinoline alkaloids obtained from Cinchona bark. They are effective blood schizonticidal agents active against all four species of malaria parasites (Plasmodium falciparum, P. vivax, P. ovale and P. malaria). They are also gametocidal for all species except P. falciparum. Their mechanism of action was thought to be by intercalation into parasite DNA, thus inhibiting DNA and RNA synthesis. Now it is believed that the activity is due to complexation with malarial pigment. Plasmodia derive essential amino acids from the degradation of host erythrocyte hemoglobin. Since ferritoprotoporphyrins (a hemoglobin degradation product) are toxic to membranes, the parasite sequesters these products as hemazoin (the malarial pigment). Quinine forms a complex with ferritoprotoporphyrin IX; preventing hemazoin sequestration and resulting in cell lysis. Quinine also affects mammalian lysosomes causing significant adverse effects. See, Angerhofer, C. K.; Konig, G. M.; Wright, A. D.; Sticher, O.; Milhous, W. K.; Cordell, G. A.; Farnsworth, N. R.; Pezzuto, J. M. 1992 In: Advances in Natural Product Chemistry, pp311-329. ed. by Atta-ur-Rahman. Harwood Academic Publishers, Gmbh, Chur.; Stahl, P.; Schwartz, A. L. J. Clin. Invest. 1986, 77, 657; c. Chaw, M.; Panosian, C. B. Clinical Microbiology Rev., 1995, 8, 427. 
Sulfadoxine (see Formula II above) is a sulfonamide. It is a blood schizonticide drug active against P. falciparum and less active against P. vivax. The only sulfone in use as a treatment for malaria is dapsone (see Formula III below) and it is similar in activity to sulfadoxine. Dapsone provides solid precedence for the potential of a clinically useful drug to exhibit activity against both Plasmodium and Mycobacterium. 
The discovery of endoperoxides as a new class of antimalarial agents began with the prototype artemisinin (see Formula IV below). Artemisinin was first isolated from an ancient Chinese herbal remedy. See, Klayman, D. L., Science, 1985, 228, 1049; Hien, T. T.; White, N. J., Lancet, 1993, 341, 603. Several semisynthetic derivatives including artemether, arteether and artesunate (see Formula V below) and the synthetic derivative arteflene (see Formula VI below), are already in development or are used clinically. See, Asawamahasakda, W.; Ittarat, I.; Pu, Y. M.; Ziffer, H.; Meshnick, S. R., Antimicrob. Agents Chemother. 1994, 38, 1854; Bradley, D. J., Trop. Med. Parasitol. 1994, 45, 259. Arteether has proven useful in high-risk malaria patients, including those with cerebral malaria. The endoperoxide moiety is necessary for antimalarial activity, since analogs that lack this group are inactive. See, Brossi, A.; Venugopaplan, B.; Gerpe, L. D.; Yeh, H. J. C.; Flippen-Anderson, J. L.; Luo, X. D.; Milhouse, W.; Peters, W., J. Med. Chem. 1988, 31, 645. b. “China Cooperative Research group on Qinghaosu and Its Derivatives as Antimalarials,” 1982, J. Traditional Med. 2, 3. The endoperoxide moiety may explain the selective toxicity to the malarial parasite, since the parasite is rich in iron and heme, which catalyze the reductive cleavage of the endoperoxide bridge, generating free radicals and other electrophilic intermediates, which in turn act as alkylating agents for specific malaria proteins. See, Meshnick, S. R.; Yang Y. -Z.; Lima, V.; Kuypers, F.; Kamchon-wongpaisan, S.; Yuthavong, Y., Antimicrob. Agents. Chemother, 1993, 37, 1108; Posner, G. H.; C. H., Oh.; Wang D.; Gerena L.; Milhouse W.; Meshnick W.; Asawamahasakda W., J. Med. Chem., 1994, 37, 1256. This process has been demonstrated in vitro in model systems and in intact parasites. Despite the clinical observation that endoperoxides are free of toxicity, evidence has been presented that some of the first generation artemisinin derivatives are neurotoxic in multidose laboratory studies. See, Brewer, T. G. Am. J. Trop. Med. Hyg., 1994, 51, 251. The origin of neurotoxicity is still under investigation; however the endoperoxide antimalarials are likely to become acceptable candidates replacing the traditional antimalarials, such as chloroquine (see Formula VII above) for which resistance is widespread. 
Current antituberculosis drugs are divisible into First-Line agents and Second-Line agents. First-line agents include the following:
1) Isoniazid (INH): (see Formula VIII below) The apparent mechanism of action of this synthetic isonicotinic acid derivative is the inhibition of mycolic acid synthesis. See, Sacchettini; J. C., Blunchard, J. S., The Structure and Function of the Isoniazid Target in Mycobacterium tuberculosis, Res. Microbiol. 1996, 147, 36-43. Mycolic acid is a peculiar, integral, structural component of Mycobacteria. INH is also reported to combine with catalase/peroxidase, an enzyme that is unique to isoniazid-sensitive strains of Mycobacteria, and results in the disorganization of cell metabolism. In response to INH treatment, saturated hexacosanoic (C26:0) was found to accumulate on a 12-kilodalton-acyl carrier protein (AcpM) that normally carried mycolic acid precursors. See, Mdluli, K.; Slayden, R. A.; Zhu, Y.; Ramaswamy, S.; Pan, X.; Mead, D.; Crane, D. D.; Musser, J. M.; Barry C. E. III, Inhibition of a Mycobacterium tuberculosis β-ketoacyl ACP Synthase by Isoniazid, Science. 1998, 280, 1607-1610. Amino acid-altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug. Resistance can occur due to the lack of catalase activity and reduced drug penetration. See, Smith, C. M.; A. M. Reynard, Treatment of Tuberculosis, In Essentials of Pharmacology, W. B. Saunders Company: Philadelphia, 1995, p 395-403. 
2) Rifampin (see Formula IX above) is a mycobactericidal and bactericidal semisynthetic derivative of rifamycin B which inhibits DNA-dependent RNA polymerase in prokaryotic, but not in eukaryotic, cells. Rifampin enters phagocytic cells and can kill intracellular, intracavitary or even dormant tuberculosis bacilli. See, Riepersberg, W. Molecular Biology, Biochemistry, and Fermentation of Aminoglycoside Antibiotics, Biotechnology of Antibiotics, 2nd Edition, Revised and Expanded, Strohl, W. R. Marcel Decker, New York, Basel, Hong Kong, 1997, p 81-163. Resistance to rifampin can occur rapidly and as a result this drug should never be administered alone.
3) Pyrazinamide (see Formula X above) is an analog of nicotinamide which is now recognized as an important first line agent in tuberculosis therapy. It is only active against intracellular organisms in macrophages at acidic pH. After phagocytosis, the organisms are contained in phagolysosomes of low pH. Pyrazinamide is usually used in combination with other drugs. See, Rang, H. P., M. M. Dale, J. M. Ritter, and P. Gardner, Antimycobacterial Agents. In Pharmacology (3rd Ed.) Churchill Livingstone, N.Y. 1995, p 738-743.
4) Ethambutol (see Formula XI above) is an ideal example of the discovery of antituberculosis agents by the in vitro screening of compounds for such activity. It is a synthetic tuberculostatic compound that acts by interfering with mycolic acid with an ill-defined mechanism. The (+) isomer is the only active form of ethambutol and it develops resistance like most other antituberculosis agents when used independently. 
5) Streptomycin (see Formula XII above) is an aminoglycoside-antibiotic. Streptomycin was the first drug available for tuberculosis but it is now the least used of the first line drugs due to its high toxicity and the rapid emergence of resistance. It is bactericidal against all Mycobacterial forms. See, Riepersberg, W. Molecular Biology, Biochemistry, and Fermentation of Aminoglycoside Antibiotics, Biotechnology of Antibiotics, 2nd Edition, Revised and Expanded. Strohl, W. R. Marcel Decker, New York, Basel, Hong Kong, 1997, p 81-163; Rost, W. J. Chemistry of the Amino Glycosides: Structure/Function Relationships, and Dworzack, D. L. Aminoglycosides: Mechanisms of Action and Resistance In: The Aminoglycoside Antibiotics: A Guide to Therapy. Barnes, W. G.; Hodges. G. R., Eds. CRC Press, Boca Raton, Fla. 1984, pp 5-22 and 23-44.
Second-Line Anti-Tuberculosis Drugs Include the Following:
1) Ethionamide (see Formula XIII above) is a synthetic congener of isonicotinic acid with bacteriostatic activity against M. tuberculosis. Ethionamide must be used in combination with other drugs. The gastrointestinal and neuropathic side effects of this material have limited the use of ethionamide.
2) p-Aminosalicylic acid (see Formula XIV above) is a synthetic bacteriostatic agent that inhibits mycobacterial growth by altering folate metabolism. It is used in the developing world, despite its toxicity, for economic reasons.
3) D-Cycloserine (see Formula XV above) is a broad-spectrum, pH-sensitive antibiotic. D-cycloserine's homology with D-alanine illustrates its competitive inhibitory activity of cell wall synthesis by preventing the formation of both D-alanine and D-alanine-D-alanine dipeptide which is added to the initial tripeptide side-chain on N-acetylmuramic acid. This prevents completion of a major block of peptidoglycan. The adverse central nervous system (CNS) effects of cycloserine restrict its application.
4) The aminoglycosides kanamycin A (see Formula XVI above), amikacin (see Formula XVII above) and peptide antibiotics; capreomycins (see Formula XVIII below), and tuberactinomycins (Viomycins) (see Formula XIX below): Cross-resistance, expense and risk of renal and ototoxicity have restricted the application of aminoglycosides and peptides as antituberculosis drugs. 
5) Ciprofloxacin and Ofloxacin are synthetic quinolones used as primary drugs in the presence of resistance to both isoniazid and rifampin. See, Ulubelen, A.; Evren, N.; Tuzlaci, E. Johansson, C. Diterpenoids from the Roots of Salvia hypargeia, J. Nat. Prod. 1988, 51, 1178-1183. The wide use of quinolones may also create resistance.
It is estimated that 1 in 100,000 to 1 in 100 million bacilli are initially resistant to any single drug used against TB. See U.S. Congress, Office of Technology Assessment, “The Continuing Challenge of Tuberculosis” OTA-H-574, Washington, D.C., U.S. Government Printing Office, September, 1993, p. 75. To combat this, the use of combination chemotherapy to treat TB has been standard practice. Initially INH, SM, and PAS are given, followed with INH, SM, and EMB, then INH and RIF. See, Simone, P. M., and Iseman, M. D., “Drug-resistant Tuberculosis: a Deadly—and Growing—Danger,” J. Resp. Dis., 1992, 13 (7), 960-971; U.S. Dept. of Health and Human Services, PHS, Centers for Disease Control and Prevention, “Initial Therapy for Tuberculosis in the Era of Multidrug Resistance, recommendations of the Advisory Council for the Elimination of Tuberculosis,” Morbidity and Mortality Weekly Report, 1992, 42 (RR-7), 1-8; Villarino, M. E., Geiter, I. J., and Simone, P. M., “The Multidrug Resistant Tuberculosis Challenge to Public Health Efforts to Control Tuberculosis,” Public Health Reports, 1992, 107 (6), 616-625. Such a multidrug procedure is estimated to be adequate for over 95 percent of TB patients. See, Bloch, A. B., Medical Officer, Surveillance and Epidemiology Branch, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, PHS, U.S. Health and Human Services, Atlanta, Ga., notes from the Advisory Committee for the Elimination of Tuberculosis Meeting, 1992. The remaining 4 to 5 percent are resistant to 2 or more drugs, and cases of resistance to as many as 11 drugs have been documented. See Goble, M., Iseman, M. D., Madsen, L. A., et al., “Treatment of 171 Patients With Pulmonary Tuberculosis Resistant to Isoniazid and Rifampin,” New England J. Med., 1993, 328 (8), 527-532.
Outbreaks of drug-resistant TB are not entirely new, (see, Reeves, R., Blakey, D., Snider, S. E., et al., “Transmission of Multiple Drug Resistant TB: Report of a School and Community Outbreak,” Am. J. Epidem., 1981, 113, 423-435; U.S. Dept. of Health and Human Services, PHS, Centers for Disease Control and Prevention, “Outbreak of Multidrug Resistant Tuberculosis—Texas, California, and Pennsylvania,” Morbidity and Mortality Weekly Report, 1990, 32 (40), 521-523) but such outbreaks have become more common, larger in scope, and more dangerous. Since 1990 there have been at least 9 outbreaks of MDR-TB in the United States, (see, U.S. Dept. of Health and Human Services, PHS, Centers for Disease Control and Prevention, “Program Briefing, 1992: Tuberculosis Elimination,” U.S. Dept. of Health and Human Services, Atlanta, Ga., unpublished report, Mar. 9, 1993) with at least seven others reported but not investigated. Most, although not all, individuals who developed active MDR-TB in these outbreaks were HIV-seropositive. The majority (79 to 89 percent) of the individuals affected by these outbreaks died from the disease and have included health care workers and prison guards. According to a press release from the World Health Organization (WHO), the incidence of drug-resistant Mtb has dramatically increased worldwide. According to the NIAID, M. tuberculosis strains resistant to two or more first-line drugs have been detected in more than 100 countries and territories. See, “Reuters Medical News” ® http://id.medscape.com/reuters/prof/2000/03/03.24/pb03240a.html. This rising prevalence of MDR-Mtb and the complexities of treating Mtb in patients with HIV have heightened the need for new anti-Mtb drugs.
Secondary metabolites isolated from natural sources, predominantly microorganisms and plants, have provided mankind with many of the therapeutic agents currently on the market. These natural products have been used directly as drugs, or have provided leads for the-synthetic preparation of pharmaceutical products. Currently, 37% of sales in the pharmaceutical industry come from products derived from natural sources. See, Joffe, S. and Thomas, R., Ag. Biotech. News Inform. 1989, 1, 697. Approximately 60% of those compounds commercially available or in the late stages of clinical trials for the treatment of infectious diseases or cancer are of natural product origin. See, Cragg, G. M.; Newman, D. J.; Snader, K. M. “Natural Products in Drug Discovery and Development” J. Nat. Prod. 1997, 60, 52-60. In recent years, a small group of researchers have isolated over 12,000 novel compounds from marine invertebrates, algae, and microorganisms. See, Faulkner, D. J., Nat. Prod. Reps. 1992, 9, 323, (And previous reports in this series) Over a dozen of these compounds (aplidine, aplyronine, dolastatin 10, bryostatin, ecteinascidin 743, kahalalide F, halichondrin B, lamellarine N, sarcodictyins, thiocaroaline, spongistatins, etc.) are in early clinical or late preclinical development. See, Shu, Y. “Recent Natural Products Based Drug Development: A Pharmaceutical Industry Perspective” 1998, 61, 1053-1071, Urban, S.; Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G.; Kelly, M. “Bioactive Marine Alkaloids,” Current Org. Chem. 2000, 4, 765-807.